tbuckley/cabot-search huggingface dataset:
A multi-center, prospective, observational study of patients with prostate cancer being treated with relugolix: OPTYX.
Authors: Daniel Eidelberg Spratt, Rana R. McKay, Tanya B. Dorff, Benjamin H Lowentritt, Mark Fallick, Sarah Hanson, Ashley Ross
Journal: Journal of Clinical Oncology (2023)

TPS398 Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) receptor agonists or antagonists are the foundation of advanced prostate cancer (aPC) treatment. Relugolix is an oral non-peptide GnRH receptor antagonist approved in the US for the treatment of aPC. In the phase 3 HERO trial, relugolix maintained suppression of testosterone to castration levels in 96.7% of men from Day 29 to 48 weeks, with superiority to leuprolide acetate. Relugolix was well tolerated and associated with a 54% lower risk of major adverse cardiovascular events relative to leuprolide acetate (Shore N, NEJM 2020;382;23). The goal of this current study (OPTYX) is to generate real-world evidence about the safety and effectiveness of relugolix in patients with prostate cancer during routine clinical care. Methods: This prospective observational cohort study (registry) is enrolling patients who have planned initiation with relugolix within 1 month prior to the time of study enrollment. The study is designed to prospectively understand the actual experience of patients with prostate cancer treated with relugolix through data collection on patients selected for treatment, treatment patterns, adherence, patient reported quality of life (QoL) and safety data. Additionally, a better understanding of the trajectory of patients with prostate cancer following cessation of relugolix therapy will be gained by observing the clinical course of the disease, health outcomes, and health-related quality-of-life (HRQoL) in these patients. Inclusion criteria include patients &gt; 18 years old with prostate cancer and planned total treatment with relugolix of at least 4 months. Estimated enrollment is 1000 patients, and patients will be followed for up to 5 years. In addition to assessing routine clinical care and disease progression, patient reported outcomes will be assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) for HRQoL and Simplified Medication Adherence Questionnaire (SMAQ) for adherence at 3 and 6 months then every 6 months. Clinical trial information: NCT05467176 .
Real-world outcomes of docetaxel (DOC) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC): First analysis from an Italian multicenter observational study (ECHOS trial).
Authors: Orazio Caffo, Umberto Basso, Nicolò Cavasin, Gaetano Facchini, Fabio Catalano, Maurizio Nicodemo, Mariella Sorarù, Paola Ermacora, Luca Galli, Carlo Cattrini, Nicolo Borsellino, Zuzana Sirotova, Sabrina Rossetti, Francesco Grillone, Paolo Andrea Zucali, Cinzia Ortega, Riccardo Ricotta, Francesca Valcamonico, Isabella Vittimberga, Consuelo Buttigliero
Journal: Journal of Clinical Oncology (2023)

167 Background: Although CHAARTED trial suggested a survival advantage in de novo (DN) high volume (HV) mCSPC pts, the use of DOC is still debated according to the timing of either metastatic onset [relapsed (REL) vs DN] or disease burden [low volume (LV) vs HV]. In this view, it could be of interest to describe the real-world use of DOC. From 2014, ECHOS multicenter study is collecting real world data from mCSPC pts in Italy, where DOC was the only reimbursed agent until recently. Here, we present study results after first data lock at the end of 2021. Methods: We reviewed the clinical records of the mCSPC pts treated with DOC in 34 Italian Institutions. For each pt we recorded pre and post-DOC clinical history, baseline characteristics, treatment details and clinical outcomes. Results: We identified 568 pts [median age 66.5 yrs (range 43-85)]. Most of them were classified as having a DN/HV disease (78%): the remaining had a REL/LV (2.5%), a REL/HV (8.1%), and a DN/LV disease (11.5%). After a median follow-up of 22 mos, 389 pts experienced disease progression and 227 died. The survival outcomes according to the metastases timing and disease volume is reported in the table. Conclusions: Our real-world experience shows that DOC is proposed not only in DN/HV pts, but also in the other pts regardless of metastases timing and disease volume. The prognosis of DN/HV pts treated with DOC appears to be worse than in CHAARTED trial. These findings need to be confirmed by further analyses made on larger number of pts enrolled in the ECHOS trial. [Table: see text]
Association of liver metastases, tumor microenvironment, and treatment outcomes in patients with urothelial bladder cancer treated with tislelizumab.
Authors: Linlin Xu, Mo Liu, Ruiqi Huang, Xiaopeng Ma, Xikun Wu, Vanitha Ramakrishnan, Lilin Zhang, Yun Zhang
Journal: Journal of Clinical Oncology (2023)

537 Background: Tislelizumab, a humanized monoclonal antibody that targets programmed cell death protein 1 (PD-1), has shown promising activity in the treatment of advanced urothelial bladder cancer (UBC). Recent studies suggest that liver metastases (LM) are associated with reduced effectiveness of PD-1/PD-L1 therapies (Yu, et al. Nat Med. 2021;27[1]:152-164). We evaluated how LM correlate with survival outcomes and the tumor immune microenvironment in UBC patients treated with tislelizumab in the BGB-A317-204 trial (NCT04004221). Methods: Cox regression was used to evaluate the effect of LM on overall survival (OS). Other key baseline characteristics were further included as covariates in the model to investigate the adjusted effect of LM and the interactions of LM with them. Gene expression profiling and multiplex immunohistochemistry (mIHC) analysis were performed on baseline tumor samples. Gene expression differences between LM positive (LM+) and LM negative (LM–) patients were compared by Wilcoxon rank-sum test for continuous biomarkers, and Fisher’s exact test for categorical biomarkers. All P-values reported in this post-hoc exploratory analysis were descriptive, without multiplicity adjustment. A result of P&lt;0.05 was considered statistically significant. Results: A total of 113 patients were included in the analysis. LM were present in 27/113 (23.9%) of them. Cox regression analysis showed the presence of LM was a negative prognostic factor for overall survival (OS) in UBC patients treated with tislelizumab, OS (hazard ratio (HR), 3.7; 95% CI, 2.3-6.2; P&lt;0.001). The LM negative prognostic value remained unaffected after adjustment for other baseline covariates. Next, we investigated immune cell infiltration and gene expression as potential indicators of impaired response in LM+ patients included in this analysis. Significantly fewer circulating lymphocytes at baseline were found in LM+ compared to LM– patients ( P&lt;0.05), while no differences were observed in other immune cell types. Reduced expression of gene signatures of CD4 Th1 ( P&lt;0.05), CD8+T cells ( P&lt;0.05) and NK cells functions ( P&lt;0.05) within tumor tissues was observed in samples from LM+ patients. Reduced CD8+ T-cell infiltration within the tumor and the intra-tumor stroma was also observed in LM+ patients based on mIHC analysis. No significant differences were observed in tumor mutational burden level between LM+ and LM– patients. Conclusions: LM were associated with worse outcomes of UBC patients treated with tislelizumab in the A317-204 study. Diminished number and impaired function of CD8+ T cells and NK cells in the tumor microenvironment of LM+ patients may have contributed to the worse survival observed in this subset of patients. Clinical trial information: NCT04004221 .
Development and clinical validation of a novel biopsy-based six-gene signature to accurately risk-stratify men with early-stage prostate cancer to aid treatment decision making.
Authors: Agnieszka Krzyzanowska, Stephen Barron, Debra Higgins, Tony Loughman, Katherine Sheehan, Angel Chan-Ju Wang, Bozena Fender, Leah M McGuire, David Jonathan Galvin, Amanda O'Neill, Joanna Fay, Anthony O'Grady, Des O'Leary, William Watson, Anders Bjartell, William M. Gallagher
Journal: Journal of Clinical Oncology (2023)

374 Background: Prostate cancer (PCa) is diagnosed in over 1.2 million men worldwide annually, making it the second-most common non-cutaneous cancer in men. Most men have indolent PCa and can safely defer treatment with active surveillance. However, many patients are commonly treated with surgery (radical prostatectomy, RP) or radiation therapy, which are associated with a significant reduction in quality of life. Molecular signatures have been developed to assist clinicians in stratifying patients based on their risk of aggressive PCa; while these have shown promise, there remains a significant opportunity for improving prognostic capacity. Methods: A panel of fourteen prognostic genes was identified from The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) database. Gene expression was measured by reverse-transcription quantitative polymerase chain reaction in RP samples from an Irish cohort of men diagnosed with PCa and treated with RP (PCRC, n=426). Cross-validated logistic regression analysis identified a six-gene molecular risk score (MRS) with strong prognostic performance to predict aggressive PCa, i.e., adverse pathology (AP) at RP or biochemical recurrence (BCR). The MRS was combined with the Cancer of the Prostate Risk Assessment (CAPRA) score to create a molecular plus clinical risk score (MCRS). The MRS and MCRS were clinically validated in biopsy samples from an independent Swedish cohort of men diagnosed with PCa and treated by RP (UPCA, n=100). Results: We identified a six-gene signature, consisting of four prognostic and two reference genes, with improved prognostic value over clinical features. In the clinical biopsy validation study univariable analysis, the AUC of the signature for AP was 0.72 (MRS) and 0.82 (MCRS) versus 0.72 for EAU risk categories and 0.82 for CAPRA. The C-index for BCR was 0.62 (MRS) and 0.74 (MCRS) versus 0.65 for EAU risk categories and 0.73 for CAPRA. Furthermore, in bivariable analysis, the six-gene signature added statistically significant (p &lt; 0.001) prognostic value to EAU risk categories and CAPRA. Conclusions: The six-gene prognostic signature has strong performance for AP and BCR in an independent clinical biopsy validation study. MCRS can provide improved prognostic stratification and inform optimal patient management post-diagnosis.
Atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem for first-line (1L) treatment (tx) of locally advanced or metastatic urothelial carcinoma (mUC): Final OS from the randomized Phase 3 IMvigor130 study.
Authors: Matt D. Galsky, Jose Angel Arranz Arija, Maria De Santis, Ian D. Davis, Aristotelis Bamias, Eiji Kikuchi, Xavier Garcia del Muro, Se Hoon Park, Ugo De Giorgi, Boris Alekseev, Marina Mencinger, Kouji Izumi, Javier Puente, Jian-Ri Li, Peter H. O'Donnell, Sandrine Bernhard, Chooi Peng Lee, Fabiola Bene-Tchaleu, Sanjeev Mariathasan, Enrique Grande
Journal: Journal of Clinical Oncology (2023)

LBA440 Background: The IMvigor130 primary analysis demonstrated statistically significant PFS benefit with 1L atezo + plt/gem (Arm A) vs placebo + plt/gem (Arm C) in pts with mUC (Galsky Lancet 2020). Interim data showed improved OS with Arm A vs C but did not cross the pre-specified threshold for significance (Galsky Lancet 2020; Galsky AACR 2021). In exploratory analyses, OS improved when atezo was combined with cisplatin (cis) vs carboplatin (carbo) regardless of PD-L1 status. Here, we report final OS data from Arms A and C. Methods: Pts were randomly assigned 1:1:1 to Arm A, B (atezo alone) or C. Arm A and C pts received cis or carbo per investigator (INV) choice. Co-primary endpoints were PFS per INV RECIST 1.1 and OS (Arm A vs C), and OS (Arm B vs C), tested hierarchically. Safety, ORR and DOR, disease control rate (DCR; confirmed CR, PR or [SD ≥ 6 mo]) and pre-specified exploratory OS data are also reported. Results: As of data cutoff Aug 31, 2022 (49 mo since last pt randomly assigned), in ITT pts, OS benefit was not statistically significant; in the cis subgroup, HR was 0.76 (95% CI 0.57, 1.01; Table). In ITT pts, DCR was 65% (290/447) in Arm A and 60% (239/397) in Arm C. 81% of safety-evaluable pts (370/454) in Arm A and 80% (312/389) in Arm C had a Gr 3/4 tx-related AE (TRAE). Gr 5 TRAEs occurred in 9 pts (2%) in Arm A and 4 (1%) in Arm C; Gr 3/4 AEs of special interest were seen in 41 pts (9%) in Arm A and 17 (4%) in Arm C. Conclusions: In this final analysis, improved OS with atezo + plt/gem vs placebo + plt/gem did not reach statistical significance in ITT pts with mUC. As seen with prior exploratory data, improved OS with atezo + plt/gem was greater when pts received cis vs carbo. No new safety signals were seen. Clinical trial information: NCT02807636 . [Table: see text]
Phase 1/2 study of EPI-7386 in combination with enzalutamide (enz) compared with enz alone in subjects with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Andrew Leonard Laccetti, Gurkamal S. Chatta, Nicholas Iannotti, Christos Kyriakopoulos, Karen Villaluna, Ronan Le Moigne, Alessandra Cesano
Journal: Journal of Clinical Oncology (2023)

179 Background: EPI-7386 is a next generation aniten designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain (NTD) of the AR while effectively blocking transcription despite AR resistance mechanisms driven by the ligand-binding domain (LBD), including point mutations and splice variants. Preclinical models demonstrate the combination of EPI-7386 with enzalutamide (enz) results in a deeper blockade of the AR pathway (per RNAseq and ChIPseq data) and greater antitumor activity, prompting initiation of this trial. Methods: This Phase 1/2 multicenter, open-label clinical trial (NCT05075577) is enrolling mCRPC pts on androgen deprivation therapy and naïve to second-generation antiandrogens (one line of prior chemotherapy allowed). Phase 1 (P1) of the trial examines escalating doses of EPI-7386 in combination with a fixed dose of enz. The primary and secondary endpoints of P1 are to evaluate the safety and pharmacokinetics (PK) aspects of EPI-7386 and enz when administered in combination to establish the recommended Phase 2 combination doses (RP2CDs) and address any possible drug-drug interactions. Once the RP2CDs are established, Phase 2 of the trial will commence as a two -arm, 2:1 randomized trial evaluating the antitumor activity of EPI-7386 in combination with enz versus enz alone. Results: Seven pts have been enrolled in the first 2 cohorts: 3 in cohort 1 (600 mg QD EPI-7386 + 120 mg QD enz) and 4 in cohort 2 (800 mg QD EPI-7386 + 120 mg QD enz). No DLTs were observed, and the safety profile was consistent with second-generation antiandrogens (e.g., Grade 1 or 2 AEs of fatigue and hot flashes). PK results demonstrated enz exposure was minimally impacted by EPI-7386, while, as expected, EPI-7386 exposure was reduced 60-80% by enz (well-established CYP3A4 inducer). The observed EPI-7386 exposures remained in the clinically relevant range suggested by preclinical xenograft studies. 4/6 evaluable patients showed a PSA decrease &gt;90% at/before week 12 regardless of the pt’s previous chemotherapy status and 5/6 evaluable patients achieved a PSA decrease of at least 85%; all 6 patients showed stable disease by imaging. Conclusions: With no safety concerns from cohorts 1 and 2, cohort 3 is enrolling at 600 mg BID EPI-7386 + 120 mg QD enz to assess if the exposure of EPI-7386 can be further increased in light of the augmented metabolism of the drug induced by enz. Clinical trial information: NCT05075577 .
Alliance A031902 (CASPAR): A randomized phase (ph) 3 trial of enzalutamide with rucaparib/placebo in first-line metastatic castration-resistant prostate cancer (mCRPC).
Authors: Arpit Rao, Glenn Heller, Charles J. Ryan, David James VanderWeele, Lionel D Lewis, Alan Tan, Colleen Watt, Ronald C. Chen, Manish Kohli, Pedro C. Barata, Benjamin Adam Gartrell, Robert Grubb, Amylou C. Dueck, Yujia Wen, Michael J. Morris
Journal: Journal of Clinical Oncology (2023)

TPS277 Background: Despite a growing number of treatment options for first-line mCRPC, approximately 40% of patients (pts) have radiographic progression within the first year. Co-inhibition of androgen receptor (AR) and PARP is a promising therapeutic strategy that leverages synthetic lethality induced by impaired double-strand DNA repair. Two phase III studies have shown improvement in radiographic progression-free survival (rPFS) in HRR-mutant pts with abiraterone + PARPi combinations vs abiraterone alone. However, the results in HRR-wild type pts are conflicting, with only one of the studies demonstrating a benefit with the abiraterone + PARPi combination. ENZ + RUCA has shown an acceptable safety profile &amp; no significant drug-drug interactions (S-DDI) in a phase 1b trial. This allows its evaluation in mCRPC. Methods: CASPAR (A031902) is a phase 3 study in which 984 pts will be randomized on a 1:1 basis to ENZ plus RUCA/PBO. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue is available). Treatment will be continued until disease progression and crossover is not allowed. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or non-measurable disease per RECIST 1.1, no prior treatment for mCRPC (prior docetaxel, abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, and no medications with S-DDI with ENZ/RUCA. Hierarchical co-primary endpoints are overall survival (OS) and rPFS. The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 and 21 months in control and combination arms, respectively), and 80% power to detect an HR of 0.80 in OS (median OS of 32 and 40 months, respectively). Key secondary endpoints are rPFS and OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 alterations; and differences in adverse events and quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF), and EQ-5D-5L. A key correlative endpoint is the sensitivity of ctDNA testing for HRR gene alterations. Enrollment began in July 2021 &amp; the study is available for participation to all US-NCTN sites. Clinical trial information: NCT04455750 .
DASL-HiCaP: A randomized, phase 3, double-blind trial of darolutamide with androgen-deprivation therapy and definitive or salvage radiation for localized very high-risk prostate cancer.
Authors: Tamim Niazi, Sean Matthew McBride, Scott Williams, Ian D. Davis, Martin R. Stockler, Andrew James Martin, Hans T. Chung, Felicia Roncolato, Annie Ebacher, Eric Khoo, Jarad Martin, Tee Sin Lim, Simon Hughes, David Pryor, James W.F. Catto, Paul Kelly, Leily Gholam Rezaei, Scott C. Morgan, Ricardo A. Rendon, Christopher Sweeney
Journal: Journal of Clinical Oncology (2023)

TPS396 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analogue (LHRHA), is a standard of care for patients with very high-risk localized prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of patients with very high-risk features. Darolutamide is a structurally distinct oral androgen receptor antagonist with low blood-brain-barrier penetration, a demonstrated favorable safety profile, and low potential for drug-drug interactions. Our aim is to determine the efficacy of adding darolutamide to ADT and RT used either as primary definitive therapy, or as salvage therapy, for very high-risk PC. Methods: This study is a randomized (1:1), phase 3, placebo-controlled, double-blind, international trial for patients planned for RT who have very high-risk localized PC on conventional imaging; or very high-risk features with PSA persistence or rise within one year following RP. The trial is stratified by previous RP; planned use of adjuvant docetaxel; clinical or pathological pelvic nodal involvement. 1100 participants will be randomized to receive darolutamide 600 mg or placebo twice daily for 96 weeks in combination with SOC (LHRHA for 96 weeks, plus RT starting week 8-24 from randomization). Participants are allowed nonsteroidal antiandrogen in addition to LHRHA for up to 90 days prior to randomization. Early treatment with up to 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival, with secondary endpoints of overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety, and resistance to study treatment. Clinical trial information: NCT04136353 .